1. Field of the Invention
This invention relates to a novel, spherical, subcutaneously implantable pellet containing estradiol, estradiol benzoate, or mixtures (hereafter sometimes referred to as the drug) thereof which exhibit a substantially constant release rate over a period of time and a substantially abrupt termination of drug release at the end of that period of time. The pellet has a biocompatible, spherical inert core which is uniformly covered by a drug/carrier composition, the diameter of the core being more than 50% of the diameter of the spherical pellet. The invention further relates to a process for administering the drug at a substantially constant rate to an animal by implanting the novel pellet of this invention into the animal.
2. Prior Art
A substantial body of literature exists which describes dosage forms of drugs which exhibit some type of controlled release mechanism. Useful discussions of prolonged action oral pharmaceuticals as well as implanted solid drug pharmaceuticals are discussed in Remington's Pharmaceutical Sciences, 14th Edition, Chapter 89 entitled "Prolonged Action Pharmaceuticals" by Burton E. Ballard and Eino Nelson, Mack Publishing Company, 1970 as well as in Patents For Prolonged Action Dosage Forms, Edward Stemple, Drug and Cosmetic Industry, 98, Nos. 1 and 2, January, 1966, pgs. 44-46 and 118-123 and February, 1966, pgs. 36-38, 139-142, 145, 146, and 148. A discussion of recent theories behind absorption of an implanted solid drug are discussed in "Absorption of Implanted Solid Drug", Ballard and Nelson, J. Pharm. Sci., Vol. 51, No. 10, pgs. 915-924, October, 1962. From this background information as well as the patent literature it is clear that subcutaneous pellet implants are known in the art and generally may be categorized as either diffusion matrix pellets, diffusion barrier pellets, or dissolution pellets.
Examples of diffusion matrix implants may be found in U.S. Pat. Nos. 3,565,991 to Short; 3,577,512 to Sheppard et al; and 3,737,521 to Born. In these patents a drug is dispersed throughout a polymer which is implanted in the body and this drug is leached or diffuses from the polymer matrix in which it is dispersed. Generally the diffusion matrix formulation results in the release rate of the drug which may be substantially constant over a first period of time but which eventually diminishes as the drug is released from the formulation. In many formulations of this type substantial amounts of drug may remain in the matrix even after it has become inactive.
Representative descriptions of dissolution implant pellet formulations may be found in U.S. Pat. No. 3,428,729 to Anderson et al and U.S. Pat. No. 2,895,875 to Klette. The Anderson et al patent is a diethylstilbestrol implant formulation which shows a decreasing rate of release, whereas the Klette patent discloses an implant which comprises an inner core of coarse hormone crystals surrounded by a layer of smaller water soluble hormone crystals in a binder such as methylcellulose. The Klette invention results in a shock like effect when the outer small particles are quickly dissolved in the body fluid but a prolonged effect due to the coarse inner crystals. Thus, there are two entirely different rates of release, whereas in a preferred aspect of this invention, a substantially constant release rate may be obtained. Dissolution pellets exhibit the disadvantage of a decreasing rate of release as time progresses. Also more drug is utilized in the pellet than is delivered at an effective level because of the decreasing rate. A cattle bolus having an inert, high density core and active ingredients surrounding it is described in British Pat. No. 936,386.
An example of a diffusion barrier implant may be found in U.S. Pat. No. 3,279,996 to Long and Folkman. In this design a drug is placed in the lumen of a tube of polydimethysiloxane and the ends of the tube are sealed. The tubing wall thickness and surface area of the tube determine the rate of release for a given drug.
With any of the known prior art dosage forms certain difficulties have been encountered. For example in the case of dissolution pellet formulation it is found that the rate of release changes substantially over the period of time in which the pellet is placed in the animal body. It is believed that the declining rate of release is due at least in part to a decrease in the size of the pellet and a consequent decrease in the area of the pellet available to be acted upon by the body. Thus, the rate of release of the drug from the pellet is very high at the beginning of the implantation but becomes very low as the time progresses. In order to administer an average amount over the time period the pellet is designed to give a greater amount than is needed over the first period of time and substantially less than the optimum amount over later period of time when the release rate decreases substantially.
On the other hand in the diffusion matrix formulation although the rate of drug release might be maintained at a fairly constant rate, these generally have the disadvantage that there is often a large quantity of drug which is left in the matrix which does not diffuse out at the optimum rate but leaches out only very slowly. Thus, this particular type of implant may utilize more drug than is required in order to get the proper release rate. This results in an economically disadvantageous product since more drug is employed in the pellet than is actually administered to the animal.
The diffusion barrier implant described in the Long and Folkman patent has the disadvantage of being difficult to prepare in that the active ingredient must be placed inside the small diameter tube, a mechanically difficult task. Further polysiloxane is expensive.
It is generally known that pellet implants having the shape of a cylinder or a disc may be used for the treatment of animals. For example Synovex.RTM.H, a commercial product marketed by Syntex Laboratories is a cylindrical shape, while U.S. Pat. No. 3,499,445 to Reed describes a disc shaped depot which is adapted for encasement by a foraminous device and subsequent subcutaneous implantation.
It has now been discovered, however, that it appears that the body reacts adversely to subcutaneous implants which have sharp edges on the implant such as the corners of discs or cylinders and that a greater degree of encapsulation of the implant is seen which causes the drug to be released from the implant relatively unevenly. Further, the disc used as a subcutaneous implant offers certain disadvantages in that it is difficult to manufacture a disc which exhibits sufficient structural integrity to withstand the forces of the body acting on the disc. Because of this lack of structural integrity, the Reed U.S. Pat. No. 3,449,445 patent teaches that its necessary to enclose a disc by a protective device so that when the disc disintegrates the pieces will be retained by the foraminous encasing device. Further, it is nearly impossible to implant a disc by any means other than by surgery since the pressures on the discs of questionable structural integrity may result in the disc breaking before even being implanted if a simple injection device is used such as that described in U.S. Pat. No. 2,761,446.
Surprisingly, it has been found that by administering estradiol, estradiol benzoate, or mixtures thereof according to the process and composition of this invention, less total drug is needed to produce a weight gain equivalent or better to that obtained by using a mixture of estradiol benzoate and progesterone (SYNOVEX-S).
The uniquely formulated pellet of this invention offers the following advantages over the prior art:
The pellet exhibits a substantially constant rate of release of drug over the life of the pellet; PA1 There is an abrupt termination of drug release at the end of the life of the pellet; PA1 Substantially no active drug remains in the pellet at the site of implantation at the end of the life of the pellet; PA1 There is less encapsulation of the pellet; PA1 The pellet is easily prepared; PA1 A reduction of total administered dose of drug may be attained; PA1 The pellet may be easily implanted using simple injection devices, surgery is not required; PA1 Surgery is not required to terminate administration of the drug.